tbuckley/cabot-search huggingface dataset:
KS04.5.A Development of a somatostatin receptor type 2 (SSTR2)-targeted probe for near infrared fluorescence guided meningioma surgery
Authors: G Fürtjes, M Weitzenberg, B Arús, H Rolbieski, C Mawrin, R Goldbrunner, O Plettenburg, O Bruns, V Neuschmelting
Journal: Neuro-Oncology (2022)

Abstract Background Meningioma mostly recur at the primary resection bed requiring improvement in the intraoperative tumor visualization and surgical technique. This study aims to develop a highly specific and sensitive optical probe for intraoperative meningioma imaging to guide the tumor resection. Fluorescent dyes in the near infrared (NIR I, 700-1000nm) and shortwave infrared (NIR II, 1000-2000nm) allow detection by suitable cameras up to few millimeters in depth in real time. Our objective is to invent a fluorescent NIR I and II probe specifically targeting the somatostatin receptor type 2 (SSTR2) reliably overexpressed in meningioma independently of WHO grade and subtype. Material and Methods By linking a somatostatin analogue (TATE, Tyr(3)Thr(8)-Octreotid) to a new developed dye (sNIR), we synthesized a SSTR2 specific probe. Its optical properties are comparable to indocyanine green and stability as well as bleaching kinetic were observed in vitro. The probe was intravenously injected in native mice to evaluate pharmacokinetics and biodistribution and detected by a custom-built camera setup focusing on physiologically highly expressing SSTR2 tissues validated by immunohistochemistry (IHC). As proof-of-principle fluorescence guided tumor resection was performed in an ectopic and orthotopic meningioma IOMM-Lee mouse model. Results The SSTR2-sNIR probe is stable in aqueous solution up to 12h with favorable optical properties regarding kinetics, biodistribution and photostability compared to its IRDye800 analogue. In vivo, we observed a highly specific physiological signal uptake in the gastric epithelium, the pancreas and pituitary (they are highly expressing SSTR2 on IHC) compared to autofluorescence and negative controls (unlabeled dye and scrambled version). Given the moderate SSTR2 expression in the preclinical meningioma model we could still detect a mean tumor-to-brain ratio of 6.12 (n = 5; SD 1.8) in the orthotopic meningioma mouse model, allowing the fluorescence guidance to be feasible. Conclusion Our preclinical results demonstrate that the innovative SSTR2-targeted fluorescent probe is stable in various biological media over time and capable of specifically targeting the SSTR2 in vitro and in vivo potentially enabling sensitive and specific meningioma fluorescent guided surgery in the future.
P07.11.A Impact of awake craniotomy on extent-of-resection and performance in glioma: a retrospective, propensity-score matched cohort study
Authors: S J P Schnitzler, T van der Vaart, K van Garderen, M J van den Bent, A J P E Vincent
Journal: Neuro-Oncology (2022)

Abstract Background The goal of awake craniotomy is to safely optimize the extent-of-resection in patients with glioma. Lower postoperative tumor volume is associated with better overall survival, emphasizing the importance of optimal surgical resection. Awake craniotomy causes less postoperative neurological deficits than surgery under general anesthesia, however, it is unclear whether awake craniotomy leads to lower postoperative tumor volume compared with general anesthesia in presumed lower grade glioma. Methods Retrospective, matched cohort study in patients with astrocytoma, IDH-mutant grade 2 and 3, oligodendroglioma, IDH-mutant, and 1p/19q-codeleted grade 2 and 3, and low-grade glioma, IDH-wildtype (now designated glioblastoma, IDH-wildtype), who underwent resection with awake craniotomy or under general anesthesia between 2003 and 2021 at Erasmus MC Brain Tumor Center. Pre- and postoperative tumor volumes were measured by semi-automatic 3D MRI-segmentation. First, we performed a multivariate logistic regression to assess which factors predicted selection for awake craniotomy. Thereafter, matching based on propensity score was attempted. Outcome variables were postoperative tumor volume, resection percentage and Karnofsky Performance Status (KPS) 3 months after surgery. Results We identified 181 awake craniotomy-patients and 135 general anesthesia-patients. Awake craniotomy-patients were younger, in better condition, more often male, with tumors more often in eloquent areas, in the left side of the brain and non-contrast enhancing. When performing matching without replacement, only 68 awake craniotomy-patients could be matched with 68 general anesthesia-patients, underscoring the imbalance in the dataset. Matching with replacement yielded a matched dataset of 181 awake craniotomy-patients with 60 general anesthesia-patients with adequate matching on most baseline variables, except for eloquent area (47% for awake craniotomy and 21.7% for general anesthesia, p &amp;lt; 0.001). In this matched dataset, median postoperative volume in awake craniotomy was 5.8 mL (IQR 0 - 92.8) vs 12.2 mL (IQR 0 - 90.1) in general anesthesia (p-value = 0.114). Resection percentages did not differ between the awake craniotomy- and general anesthesia-groups. KPS scores at 3 months after surgery did not differ between awake craniotomy and general anesthesia (p = 0.15). Conclusion Postoperative tumor volume was not lower in awake craniotomy-patients than in general anesthesia-patients. Neither were resection percentage and KPS scores at 3 months after surgery significantly different between the groups. Adequate matching was only obtainable using replacement, underscoring the risk of bias in unmatched datasets. These data should be interpreted with care, given the retrospective nature, potential residual confounding and potential lack of generalizability due to unmatched normal resection patients.
P09.05.A Caregiver café in a neuro-oncological context
Authors: M Mathiasen, C Bang Rasmussen, K Piil
Journal: Neuro-Oncology (2022)

Abstract Background Caregivers to patients with primary brain tumors often play a vital role in the direct care and support of the patient. Great responsibility is placed on their shoulders to manage practicalities during the cancer trajectory. Caregivers are asked to carry out procedures, report patient-related evaluations, coordinate care and treatment and deliver proper information to the healthcare providers. Hence, they tend to neglect their own physical and emotional needs as they priorities other tasks including financial issues, household and work while coping with family adjustment. Caregivers of patients with brain tumors experience a high level of burden and distress. It is shown in literature that caregiver interventions can reduce caregiver burden, distress and anxiety, and improve coping, relationships and physical functioning Aim: The aim of this study is to offer caregivers to join a caregiver café at the neuro-oncological department to 1) relax, meet and support each other, (2) be provided with information and answers to their questions, and (3) be recommended appropriate caregiver services. Material and Methods This is a user-based sequential three phase project. Applying a co-creation process with informal caregivers we first investigate their preferences, needs and considerations in relation to establishing a caregiver café. A user survey consisting of demographic characteristics and five study-specific and open-ended questions are conducted. Secondly, a project protocol with the design, content and practical planning will be outlined and presented for the patient/relative-user panel at the oncological department. After the final adjustment, a feasibility testing will take place in phase three. Results This three-phase project rest on a sequential project development, and findings from one phase will led to the detailed adjustment in the next. Due to its nature of following a participatory design we consider the results to be highly relevant to the users of health-care services. Results from phase I and II is ready to be presented in autumn 2022 including the preliminary results of the feasibility study (recruitment, adherence, safety etc). Conclusion Nurses working within neuro-oncology are e.g responsible for providing support, information and education for family caregivers. This project may inspire other nurses to carry out similar initiatives in clinical practice. Thereby we seek to strengthen the evidence on how, what and when the caregivers’ needs and concerns are best addressed with innovative solutions. Acknowledgement We like to thank the nurses at the neuro-oncology department, Rigshospitalet for their valuable input and for their participating with the user survey.
P14.01.B Isolation and characterization of circulating tumor cells in a glioblastoma case with recurrence at distance and correlation with tumor mutational status
Authors: F Lessi, M Morelli, P Aretini, M Menicagli, S Franceschi, F Pasqualetti, C Gambacciani, A Di Stefano, O Santonocito, C M Mazzanti
Journal: Neuro-Oncology (2022)

Abstract Background Circulating Tumor Cells (CTCs) are considered to be one of the important causes of tumor recurrence and distant metastasis. For many years, glioblastoma (GB) was thought to be restricted to the brain. Nevertheless, a growing body of evidence indicates that, like many other cancers, hematogenic dissemination is a reality. The absence of a procedural uniformity in literature prompted us to develop an innovative and sensitive method to obtain CTCs in GB. Our aim is to define the genetic background of single CTCs compared with the primary GB tumor and its recurrence to assess whether or not their presence in the peripheral circulation correlates with GB migration and dissemination. Material and Methods CTCs were enriched from whole blood of one patient with recurrent GB with Parsortix Cell Separation System and analysed on DEPArray system. After that, CTCs Copy Number Aberrations (CNAs) and sequencing analysis was performed to compare CTCs genetic background with the same patient’s primary and recurrence tissues, analysed by NextSeq 500 (whole exome sequencing). Results We obtained 211 mutations in common between primary and recurrence tumor. Among these, three somatic mutations (c.430 G&amp;gt;A in PRKCB gene, c.815 C&amp;gt;T in TBX1 gene and c.1554 T&amp;gt;G in COG5 gene) were selected to investigate their presence in recurrence CTCs. Almost all of the sorted CTCs (9/13) had at least one of the mutations tested. Conclusion In confirmation of the hypothesis, the CTCs detected in the patient's blood were actually cancer cells deriving from GB tumor.
P02.03.B Drug repurposing screen reveals glioblastoma cell line susceptibility to statins
Authors: D S L Harwood, S R Michaelsen, A Anand, F Mundt, B W Kristensen
Journal: Neuro-Oncology (2022)

Abstract Background The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. Objectives: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma. Material and Methods Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achillies project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers. Results Fluvastatin and pitavastatin were amongst the drugs with the most significant effects against glioblastoma cell lines while also being FDA approved. These effects were found in both glioblastoma cells and other cancer types with a mesenchymal-like expression phenotype. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with the gene knockout of UBIAD1. We tested the effects of statins on patient-derived glioblastoma cell lines with a mesenchymal (n = 2) and non-mesenchymal phenotype (n=2). Mesenchymal-like glioblastoma cells lines were found to be more susceptible to statins. Conclusion Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to the direct or indirect inhibition of UBIAD1. In vitro validation of this finding is ongoing.
P11.33.B Tumour Treating Fields (TTFields; 200 kHz) with chemo-radiation and maintenance TTFields/temozolomide as first-line treatment for newly-diagnosed glioblastoma: The phase 3 TRIDENT Trial (EF-32)
Authors: W Shi, L Kleinberg, S A Jeyapalan, S A Goldlust, S Nagpal, D Roberge, R Nishikawa, R Grossman, M Glas
Journal: Neuro-Oncology (2022)

Abstract Background Tumour Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, loco-regional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM) and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. In 2 clinical pilot phase 2 studies, TTFields added to RT/TMZ was reported as feasible and well-tolerated. Material and Methods TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomised trial comparing TTFields (200 KHz, ≥ 18 h/day)/RT/TMZ vs RT/TMZ alone. Eligibility criteria include histologically confirmed ndGBM, ≥ 18 years of age (≥ 22 years of age; US), Karnofsky Performance Status ≥ 70, life expectancy ≥ 3 months, adequate organ function and eligible for RT/TMZ - participants will be stratified by extent-of-resection and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. During the initial 6-week investigational period, patients in the experimental arm will receive continuous TTFields and concomitant RT/TMZ whilst patients in the control arm will receive only RT/TMZ. Subsequently, all patients will receive TTFields and 6 cycles of maintenance TTFields/TMZ. TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO), whichever occurs first. The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs (Common Terminology Criteria for Adverse Events v5.0), post-treatment pathological changes in resected GBM tumours, quality-of-life per EORTC QLQ-C30, OS correlation to TTFields duration-of-usage, and neurological assessment per NANO (Neurological Assessment in Neuro-Oncology) and RANO criteria. Survival will be measured from time-of-randomisation. Sample size (N = 950; randomised 1:1) was powered for a hazard ratio &amp;lt; 0.8 with a 5% type I error. The hypothesis, that first-line TTFields/RT/TMZ can significantly improve OS vs RT/TMZ, will be tested using a stratified log-rank test. The study is currently open to enrollment in locations in Austria, Belgium, Czech Republic, France, Germany, Israel, Switzerland, and across the US.
P11.32.A EGFR expression and non-methylated MGMT predict distant recurrence in glioblastoma patients treated with standard therapy
Authors: T Urup, A K Trip, S B Chiranth, I J Christensen, K Grunnet, S Møller, B Hasselbalch, A Muhic, U Lassen, H S Poulsen
Journal: Neuro-Oncology (2022)

Abstract Background Infiltrative growth within the central nervous system is hallmark of glioblastoma (GBM) at time of diagnosis. Targeting infiltrative glioma cells by adding chemotherapy to local treatment (surgical resection and radiotherapy) has led to improved tumor control and survival. Still, infiltrative growth is a major factor in therapeutic failure and tumor recurrence is almost inevitable. Herein, we hypothesize that distant recurrence represents a more migratory phenotype and that biomarkers associated with distant recurrence can be used to personalize the treatment. The aim of this study was to identify clinical and molecular factors associated with distance recurrence in glioblastoma patients treated with standard therapy. Material and Methods A prospective cohort of consecutive, non-selected GBM patients administered standard therapy as primary treatment between 2005-2020 at Rigshospitalet, Copenhagen, Denmark. Distant recurrence was defined as a new contrast-enhancing tumor lesion outside the radiation field (&amp;gt; 2 cm from the gross tumor volume). Clinical and molecular factors were screened for association with time to distant recurrence (p &amp;lt; 0.30) using univariate analysis. The final model was generated employing multivariate Cox regression analysis to model the association with time to distant recurrence. It was chosen to maintain known prognostic factors in the model and subsequently add significantly associated factors (p &amp;lt; 0.05). Competing risk adjusted analysis were performed with death as a competing risk. Results A total of 897 patients were included and at a median follow-up time of 73 (range: 12-198) months, 733 patients were evaluable for recurrence pattern. Out of 733 patients, 146 patients (20%) had distant recurrence. Median time to tumor progression was 7.0 months for patients with a local recurrence and 8.0 months for those with a distant recurrence (p=0.31). The following prognostic factors were not associated with distant recurrence by multivariate analysis: Corticosteroid use (p=0.84), age (p=0.20), multifocal disease (p=0.81), ECOG performance status (p=0.99) and degree of tumor resection (p=0.20). In multivariate analysis, factors independently associated with a higher likelihood of distant recurrence were: Non-methylated promoter of the MGMT gene (HR=1.93; 95% CI: 1.27-2.95; p=0.002) and positive expression of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (HR=3.70; 95% CI: 1.61-8.33; p=0.002). Conclusion Non-methylated MGMT and positive expression of EGFR were independently associated with a higher likelihood of distant recurrence in GBM patients treated with standard-of-care. These factors, if validated, can be used for risk stratification and to enrich clinical treatment protocols aiming at improved local or distant tumor control.
P11.46.A Whole exome sequencing identifies novel SLIT2 mutations in primary CNS lymphoma
Authors: L D Kaulen, E Z Erson-Omay, O Henegariu, P Karschnia, A Huttner, M Günel, J M Baehring
Journal: Neuro-Oncology (2022)

Abstract Background Whole exome sequencing (WES) data on primary CNS lymphoma (PCNSL) is scarce and correlation with clinical observations is needed to facilitate personalized care. Here we present WES data of six PCNSL and correlate genetic findings with clinical outcome. Material and Methods WES was performed on paired blood and tumor DNA samples from six PCNSL patients to a median coverage of 100x (range: 73-135x) and 194x (range: 127-232x), respectively. Selected, novel mutations were validated with Sanger sequencing. Epstein-Barr virus (EBV) status was assessed in tumor tissue. Progression free survival (PFS) and overall survival (OS) were analyzed in our cohort and in an extension cohort from the cBio Cancer Genomics Portal using Kaplan-Meier method and log-rank tests. P values &amp;lt; 0.05 were considered significant. Results We found a median of 22 (range: 11-68) somatic copy number variations, 171 (range: 82-298) somatic single-nucleotide variants and 11 (range: 0-22) somatic insertions/deletions per PCNSL. CDKN2A loss, identified in five samples, was the most commonly detected copy number alteration. PCNSL carried mutations in previously described PIM1, MYD88, CD79B or BTG genes. In three PCNSL, we identified novel SLIT2 mutations (p.N63S, p.T590M, p.T732S) clustered around the leucine-rich repeats (LRR) domains. WNT-reporter and NF-kB reporter luciferase assays suggested alterations were loss-of-function variants. SLIT2 mutations were associated with shorter PFS in our cohort and with shorter OS in an extension cohort of 1856 lymphoid malignancies from the cBio Cancer Genomics Portal. Conclusion PCNSL harbored previously unknown SLIT2 mutations clustered around domains that are critical for interaction with ROBO proteins. SLIT2 mutations may be predictive of less favorable outcome in PCNSL. Additional clinical and molecular evaluation of these mutations is warranted.
P17.03.B Modelling migration of glioblastoma patient-derived cells using human iPSC-derived neural spheroid and high content analysis
Authors: V S Tsang, I Lieberam, D Danovi
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour in adults. Despite current advances, the existing standard of treatment is ineffective, and the survival prognosis remains just over a year from diagnosis. Migrating tumour cells have been implicated in the therapeutic resistance of GBM. They spread by interacting with structures such as white matter tracts and inevitably cause recurrence of the tumour. Valuable cell models able to capture the invasiveness of GBM are critically needed to develop innovative therapies targeting migrating GBM cells. Material and Methods We established an in vitro model mimicking the GBM microenvironment by co-culturing patient-derived GBM cells and human induced pluripotent stem cell-derived cortical neural spheroids with radiating axons. Using high content imaging, we developed a robust workflow to quantify the GBM cells infiltration of the neural spheroid in endpoint assays. Images were acquired on the Operetta CLS high content device (Perkin Elmer) and analysed using the built-in Harmony Imaging and Analysis Software. We also performed live imaging assays using the Livecyte quantitative phase imager (Phasefocus), in which we studied the directionality, displacement and speed of the GBM cells engaged on axons. Results Our data indicate that GBM cells change morphology when cultured on axons and that they migrated towards the neural spheroid once engaged on axons. We showed that cell lines from different patients vary in migratory properties as well as in levels of infiltration capability. Finally, we used this model to test several antagonists to pathways involved in migration of GBM cells. Conclusion The main deliverable of this project is the setup of a novel model able to mimic the GBM migration on axons and able to screen for compounds affecting cell migration. This could potentially offer innovative precision-medicine therapies.